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Neurogenetics. 2018 May;19(2):93-103. doi: 10.1007/s10048-018-0541-0. Epub 2018 Mar 6.

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Author information

1
Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
2
University of Lille, EA 7364-RADEME, Lille, France.
3
Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, avenue Eugène Avinée, Lille, France.
4
Laboratoire de diagnostic génétique, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
5
Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France.
6
Service de Génétique, Hospices Civils de Lyon, Lyon, France.
7
Service de Génétique, Hôpital d'Enfants Armand-Trousseau, AP-HP, Paris, France.
8
Department of Pathology Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
9
Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
10
Service de Génétique, CHU d'Angers, Angers, France.
11
Département de Génétique Médicale, CHU Montpellier, Montpellier, France.
12
Laboratoire de Génétique Chromosomique, CHU Grenoble Alpes, Grenoble, France.
13
Service de Génétique, EA3801, SFR-CAP Santé, CHU de Reims, Reims, France.
14
St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
15
Centre de Génétique et Centre de Référence Maladies Rares 'Anomalies du Développement, CHU Dijon, Dijon, France.
16
Equipe GAD, UMR INSERM 1231, Université de Bourgogne, Dijon, France.
17
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
18
The Genetics of Learning Disability Service, Waratah, New South Wales, Australia.
19
Service de Génétique Médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
20
Service de Génétique, Hôpital Trousseau, AP-HP, Paris, France.
21
Service de Génétique et Inserm U1079, Centre Normand de Génomique Médicale et Médecine Personnalisée, CHU de Rouen, Inserm et Université de Rouen, Rouen, France.
22
Department of Clinical Genetics, University Hospital Linköping, Linköping, Sweden.
23
Service de Génétique Médicale, Unité de Génétique Clinique, CHU de Nantes, Nantes, France.
24
Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
25
Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy.
26
Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
27
Unité Fonctionnelle de Génétique Clinique, Hôpital Robert Debré, AP-HP, Paris, France.
28
Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
29
Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
30
University of Lille, EA 7364-RADEME, Lille, France. jamal.ghoumid@chru-lille.fr.
31
Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, avenue Eugène Avinée, Lille, France. jamal.ghoumid@chru-lille.fr.

Abstract

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

KEYWORDS:

Cardiopathy; Intellectual disability; MED13L; Mediator complex

PMID:
29511999
DOI:
10.1007/s10048-018-0541-0

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